Method for asymmetric hydrogenation of tetrasubstituted alpha, beta-unsaturated carboxylic acid derivative under catalysis of nickel

Abstract

The invention relates to the technical field of chemical synthesis, and particularly discloses a method for constructing chiral 2, 3-disubstituted butyrate through asymmetric hydrogenation of tetra-substituted alpha, beta-unsaturated carboxylic acid derivatives, and chiral ester and chiral amide prepared through the method. According to the present invention, the beta-unsaturated carboxylic acid derivative is adopted as the substrate, hydrogenation is performed to construct the chiral ester and the chiral amide, the catalyst preparation method is simple, the performance is stable, and the good chiral selection effect and the good conversion rate can be obtained under the high substrate / catalyst condition; the metal catalyst is prepared from a metal nickel complex and a diphosphorus chiral ligand (R, R)-QuinoxP *. The method provided by the invention has the characteristics of high enantioselectivity, high yield and high conversion number (TON). The method can be used for synthesizing various substituted chiral esters and amides, can be used as important intermediates for preparing various medicines, and has important significance on the production of the medical industry.

Description

Technical Field

[0001] The present invention relates to the field of chemical synthesis, and in particular to a method for constructing chiral 2,3-disubstituted butyric acid derivatives through nickel-catalyzed asymmetric hydrogenation of tetrasubstituted α,β-unsaturated carboxylic acid derivatives, and chiral carboxylic acid derivatives prepared by the method. Background Art

[0002] Chiral carboxylic acids and their derivatives are a type of functional group structure that is widely found in pharmaceuticals, natural products, fine chemicals, and agrochemicals. For example, Valerate, Esfenvalerate, Implitapide, and Veliflapon shown below all contain structures of chiral carboxylic acids and their derivatives: .

[0003] Due to the enormous industrial value of chiral carboxylic acids and their derivatives in fields such as pharmaceuticals, their synthesis methods have been intensively studied, and many synthetic routes have been developed. Among them, the asymmetric reduction of potentially chiral tetrasubstituted α,β-unsaturated carboxylic acid derivatives is one of them. However, to date, no simple and efficient nickel-catalyzed asymmetric reduction method has been applied to the asymmetric reduction of tetrasubstituted α,β-unsaturated carboxylic acid derivatives. Summary of the Invention

[0004] In view of the problem that there are few technical routes for chiral 2,3-disubstituted butyric acid derivatives in the prior art, the first aspect of the present invention provides a method for asymmetric hydrogenation of tetrasubstituted α,β-unsaturated carboxylic acid derivatives to construct chiral 2,3-disubstituted butyric acid derivatives. The compound represented by formula (I) is asymmetrically hydrogenated in the presence of a catalyst Cat to obtain the compound represented by formula (II). The reaction formula is as follows: ; It is understood that the reaction further includes the solvent in order to provide a reaction medium.

[0005] The solvent used in the reaction process and the solvent of the catalyst are the same solvent, which simplifies the reaction steps.

[0006] The R 1 、R 2 is selected from a substituted or unsubstituted monocyclic carbocyclic group, a substituted or unsubstituted condensed-ring carbocyclic group, a substituted or unsubstituted spirocyclic group, a substituted or unsubstituted bridged ring, a substituted or unsubstituted monocyclic heterocyclic group, a substituted or unsubstituted condensed-ring heterocyclic group, a substituted or unsubstituted monocyclic aromatic group, a substituted or unsubstituted branched alkyl group, or a substituted or unsubstituted linear alkyl group; the catalyst Cat is prepared from a metal nickel compound and a bisphosphine chiral ligand, and the bisphosphine chiral ligand has the structure shown below, .

[0007] It is understood by those skilled in the art that the metal nickel compound and the diphosphorus chiral ligand are mixed in a solvent to obtain the obtained compound.

[0008] The solvent includes methanol, ethanol, isopropanol, tert-butanol, dichloromethane, toluene, 1,2-dichloroethane, chloroform, carbon tetrachloride, tetrahydrofuran, 1,4-dioxane, n-hexane, cyclohexane or hexafluoroisopropanol, or a combination thereof.

[0009] The above * represents a carbon chiral center, and the multiple carbon chiral centers are each independently of the R configuration or the S configuration.

[0010] The R 1 、R 2 is selected from substituted or unsubstituted monocyclic carbocyclic groups, substituted or unsubstituted fused-ring carbocyclic groups, substituted or unsubstituted spirocyclic groups, substituted or unsubstituted bridged rings, substituted or unsubstituted monocyclic heterocyclic groups, substituted or unsubstituted fused-ring heterocyclic groups, substituted or unsubstituted monocyclic aryl groups, substituted or unsubstituted branched-chain alkyl groups, and substituted or unsubstituted straight-chain alkyl groups; In some specific embodiments of the first aspect, the R 1 is a heterocyclic fused ring group, wherein R 1 A fused ring group comprising two or more first rings fused to each other; the first ring is selected from a pyrrole group, a furan group, a thiophene group, a pyrrole group, a thiorrole group, an indene group, a benzofuran group, a benzothiophene group, an indole group, and a benzothiorrole group.

[0011] In some specific embodiments of the first aspect, the R 1 is a heterocyclic fused ring group, wherein R 1 A fused ring group comprising at least one first ring fused to at least one second ring; the first ring is selected from a pyrrole group, a furan group, a thiophene group, a pyrrole group, a thiorrole group, an indene group, a benzofuran group, a benzothiophene group, an indole group, and a benzothiorrole group, and the second ring is selected from a cyclohexane group, a cyclopentane group, and a monocyclic aromatic group.

[0012] In some specific embodiments of the first aspect, the R 1 is a fused-ring carbocyclic group, wherein the fused-ring carbocyclic group is a fused-ring group in which two or more second rings are fused to each other; the second ring is selected from a cyclohexane group, a cyclopentane group, and a monocyclic aromatic group.

[0013] Preferably, the R 1is cyclohexyl, furyl, thienyl, pyridyl, naphthyl, or phenyl, wherein each of the cyclohexyl, furyl, thienyl, pyridyl, naphthyl, and phenyl groups is optionally substituted with one or more groups independently selected from nitro, fluorine, chlorine, bromine, C1-C4 alkyl, C1-C4 halo, and C1-C4 alkoxy; And / or, the R 1 is cyclohexyl, 2-furyl, 2-thienyl, 2-pyridyl, 1-naphthyl, 2-naphthyl, phenyl, 4-methylphenyl, 4-fluorophenyl, 3-fluorophenyl, 2-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-nitrophenyl, 4-trifluoromethylphenyl, 3,5-bis(trifluoromethyl)phenyl, 4-methoxyphenyl, 3-methoxyphenyl; The R 2 and R 3 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxyacylmethyl, methoxyacylethyl, ethoxyacylmethyl or ethoxyacylethyl.

[0014] In some specific embodiments of the first aspect, the ring n is selected from 1-6 straight-chain alkyl groups.

[0015] In some specific embodiments of the first aspect, the heterocyclic group has 1 to 3 heteroatoms selected from N, O, and S.

[0016] As a preferred embodiment, n is a straight-chain alkyl group of 1-6, and the structure is shown below: .

[0017] The R is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, fluorine, chlorine, bromine, or alkoxy.

[0018] In some specific embodiments of the first aspect, R2 is selected from C1~C6 substituted or unsubstituted straight-chain alkyl, or, R2 is selected from C1~C6 substituted or unsubstituted branched-chain alkyl, or, R2 is selected from C1~C6 halogenated straight-chain alkyl, or, R2 is selected from C1~C6 halogenated branched-chain alkyl, or, R2 is selected from C1~C6 alkoxy.

[0019] The R 2 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxyacylmethyl, methoxyacylethyl, ethoxyacylmethyl or ethoxyacylethyl.

[0020] Among the raw materials, the tetrasubstituted α,β-unsaturated carboxylic acid derivative is one of the structures shown below: .

[0021] In some specific embodiments of the first aspect, the metal nickel complex includes any one of Ni(OAc)2·4H2O, Ni(OAc)2, NiCl2(DME), NiBr2(DME), Ni(OTf)2, Ni(acac)2, Ni(OCOCF3)2·6H2O, and NiI2.

[0022] In some specific embodiments of the first aspect, the metal nickel complex and the diphosphorus chiral ligand are reacted in a solvent Solvent at room temperature for 0.5 hour to 12 hours to prepare the metal catalyst.

[0023] In some specific embodiments of the first aspect, the molar ratio of the metal nickel complex to the diphosphorus chiral ligand is 1.0:1.0-1.2.

[0024] In some specific embodiments of the first aspect, the solvent Solvent is methanol, ethanol, isopropanol, tert-butanol, dichloromethane, toluene, acetonitrile, ethyl acetate, trifluoroethanol, hexafluoroisopropanol, 1,2-dichloroethane, chloroform, carbon tetrachloride, tetrahydrofuran, 1,4-dioxane, n-hexane or cyclohexane, or a combination thereof.

[0025] In some specific embodiments of the first aspect, the reaction temperature of the asymmetric reduction is 0°C to 50°C. In some preferred embodiments of the first aspect, the reaction temperature of the asymmetric reduction is below 25°C.

[0026] In some specific embodiments of the first aspect, the reaction time of the asymmetric reduction is 1 h to 48 h. In some preferred embodiments of the first aspect, the reaction time of the asymmetric reduction is 48 h.

[0027] In some specific embodiments of the first aspect, the asymmetric reduction is performed in a hydrogen atmosphere at 45-55 atmospheres of pressure.

[0028] In the present invention: “Mol %” indicates the molar percentage of the substance relative to the tetra-substituted α,β-unsaturated carboxylic acid ester.

[0029] “S / C” represents the ratio of substrate to catalyst.

[0030] "Room temperature" in some embodiments represents 40°C to 10°C, in some embodiments represents 35°C to 15°C, in some embodiments represents 30°C to 20°C, in some embodiments represents 25°C to 20°C, and in other embodiments represents 25°C.

[0031] In the present invention, DMF is N,N-dimethylformamide, EA is ethyl acetate, THF is tetrahydrofuran, Hexane is n-hexane, Toluene is toluene, TFE is trifluoroethanol, and HFIP is hexafluoroisopropanol.

[0032] The advantages of the present invention are: the present invention uses tetrasubstituted α, β-carboxylic acid derivatives with different molecular structures as substrates for hydrogenation to construct chiral carboxylic acid derivatives; the catalyst used in the method is simple to prepare and has stable performance; and good chiral selectivity and conversion rate can still be achieved under high substrate / catalyst conditions. DETAILED DESCRIPTION

[0033] Through the following detailed description of the embodiments of the present invention in combination with specific implementation methods, those skilled in the art will more clearly and thoroughly understand the further features, advantages and effects of the present invention.

[0034] Example 1: Asymmetric reduction of ethyl 2-(4-methylphenyl)-3-methylbut-2-enoate

[0035] In a high-purity argon atmosphere, Ni(OAc)2·4H2O (1.0×10 -2 mmol) and ligand ( R,R )-QuinoxP*(1.1×10 -2 mmol) was dissolved in hexafluoroisopropanol (0.5 mL) and stirred at room temperature overnight to obtain an orange-red clear solution (i.e., the catalyst).

[0036] 0.5 mL of the catalyst was added to compound 1a (0.2 mmol), followed by 0.5 mL of hexafluoroisopropanol. The reaction system was placed in an autoclave and stirred at 25°C under H2 (50 bar) for 48 hours. The solvent was removed under reduced pressure, and the product was separated by column chromatography (silica gel column, eluent: petroleum ether:ethyl acetate = 10:1) to obtain product 2a. HPLC analysis of the product revealed an ee value of 99% and a yield of 96%. HPLC separation conditions: chiral OJ-H column, mobile phase: n-hexane / isopropanol = 99:1 (volume ratio), flow rate: 1.0 mL / min, wavelength: 220 nm, column temperature: 30°C. 1 H NMR (400 MHz, CDCl3) δ 7.24 (d, J = 8.1 Hz, 2H), 7.12 (d, J = 7.9 Hz, 2H), 4.02-4.20 (m, 2H), 3.11 (d, J= 10.6 Hz, 1H), 2.39 – 2.28 (m, 4H), 1.22 (t, J = 7.2 Hz, 3H), 1.05(d, J = 6.5 Hz, 3H), 0.72 (d, J = 6.7 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 174.0,136.6, 135.4, 129.0, 128.2, 60.3, 59.7, 31.8, 21.3, 20.9, 20.1, 14.1. Example 2: Asymmetric reduction of ethyl 2-(4-isopropylphenyl)-3-methylbut-2-enoate

[0037] In a high-purity argon atmosphere, Ni(OAc)2·4H2O (1.0×10 -2 mmol) and ligand ( R,R )-QuinoxP*(1.1×10 -2 mmol) was dissolved in hexafluoroisopropanol (0.5 mL) and stirred at room temperature overnight to obtain an orange-red clear solution (i.e., the catalyst).

[0038] 0.5 mL of the catalyst was added to compound 1b (0.2 mmol), followed by 0.5 mL of hexafluoroisopropanol. The reaction system was placed in an autoclave and stirred at 25°C under H2 (50 bar) for 48 hours. The solvent was removed under reduced pressure, and column chromatography (silica gel column, eluent: petroleum ether:ethyl acetate = 10:1) was performed to obtain product 2b. HPLC analysis of the product revealed an ee value of 98% and a yield of 99%. HPLC separation conditions: chiral OD-H column, mobile phase: n-hexane / isopropanol = 80:0 (volume ratio), flow rate: 1.0 mL / min, wavelength: 220 nm, column temperature: 30°C. 1 H NMR (400 MHz, CDCl3) δ 7.27 – 7.21 (m, 2H), 7.18 – 7.12 (m, 2H), 4.01-4.20 (m, 2H), 3.10(d, J = 10.6 Hz, 1H), 2.88 (q, J = 6.9 Hz, 1H), 2.26-2.36 (m, 1H), 1.22 (dd, J=8.5, 7.0 Hz, 9H), 1.03 (d, J = 6.5 Hz, 3H), 0.70 (d, J = 6.7 Hz, 3H). 13 C NMR (101MHz, CDCl3) δ 174.2, 147.6, 135.7, 128.3, 126.4, 60.4, 59.7, 33.7, 32.0,23.9, 21.4, 20.3, 14.2. Example 3: Asymmetric reduction of ethyl 2-(4-(tert-butyl)phenyl)-3-methylbut-2-enoate

[0039] In a high-purity argon atmosphere, Ni(OAc)2·4H2O (1.0×10 -2 mmol) and ligand ( R,R )-QuinoxP*(1.1×10 -2 mmol) was dissolved in hexafluoroisopropanol (0.5 mL) and stirred at room temperature overnight to obtain an orange-red clear solution (i.e., the catalyst).

[0040] 0.5 mL of the catalyst was added to compound 1c (0.2 mmol), followed by 0.5 mL of hexafluoroisopropanol. The reaction system was placed in an autoclave and stirred at 25°C under H2 (50 bar) for 48 hours. The solvent was removed under reduced pressure, and column chromatography (silica gel column, eluent: petroleum ether:ethyl acetate = 10:1) was performed to obtain product 2c. HPLC analysis of the product revealed an ee value of 95% and a yield of 80%. HPLC separation conditions: chiral OD-H column, mobile phase: n-hexane / isopropanol = 30:0 (volume ratio), flow rate: 1.0 mL / min, wavelength: 220 nm, column temperature: 30°C. 1 H NMR (400 MHz, CDCl3) δ 7.33 – 7.22 (m, 4H), 4.01-4.20 (m, 2H), 3.10 (d, J = 10.6 Hz, 1H),2.21-3.27 (m, 1H), 1.30 (s, 9H), 1.22 (t, J = 7.1 Hz, 3H), 1.03 (d, J = 6.5 Hz,3H), 0.71 (d, J = 6.7 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 174.2, 149.8, 135.3,128.0, 125.2, 60.4, 59.6, 34.4, 32.0, 31.3, 21.4, 20.3, 14.2. Example 4: Asymmetric reduction of ethyl 2-(4-methoxyphenyl)-3-methylbut-2-enoate

[0041] In a high-purity argon atmosphere, Ni(OAc)2·4H2O (1.0×10 -2 mmol) and ligand ( R,R )-QuinoxP*(1.1×10 -2 mmol) was dissolved in hexafluoroisopropanol (0.5 mL) and stirred at room temperature overnight to obtain an orange-red clear solution (i.e., the catalyst).

[0042] 0.5 mL of the catalyst was added to compound 1d (0.2 mmol), followed by 0.5 mL of hexafluoroisopropanol. The reaction system was placed in an autoclave and stirred at 25°C under H2 (50 bar) for 48 hours. The solvent was removed under reduced pressure, and the product was separated by column chromatography (silica gel column, eluent: petroleum ether:ethyl acetate = 10:1) to obtain product 2d. HPLC analysis of the product revealed an ee value of 98% and a yield of 96%. HPLC separation conditions: chiral OJ-H column, mobile phase: n-hexane / isopropanol = 99:1 (volume ratio), flow rate: 1.0 mL / min, wavelength: 220 nm, column temperature: 30°C. 1 H NMR (400 MHz, CDCl3) δ 7.32 – 7.23 (m, 2H), 6.92 – 6.80 (m, 2H), 4.24 – 4.01 (m, 2H), 3.81 (s, 3H), 3.09 (d, J = 10.6 Hz, 1H), 2.26-2.35 (m, 1H), 1.24 (t, J = 7.1 Hz, 3H),1.05 (d, J = 6.5 Hz, 3H), 0.72 (d, J = 6.7 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ174.2, 158.7, 130.6, 129.4, 113.7, 60.4, 59.2, 55.2, 31.9, 21.4, 20.2, 14.1. Example 5: Asymmetric reduction of ethyl 3-methyl-2-(m-tolyl)but-2-enoate

[0043] In a high-purity argon atmosphere, Ni(OAc)2·4H2O (1.0×10 -2 mmol) and ligand ( R,R )-QuinoxP*(1.1×10 -2 mmol) was dissolved in hexafluoroisopropanol (0.5 mL) and stirred at room temperature overnight to obtain an orange-red clear solution (i.e., the catalyst).

[0044] 0.5 mL of the catalyst was added to compound 1e (0.2 mmol), followed by 0.5 mL of hexafluoroisopropanol. The reaction system was placed in an autoclave and stirred at 25°C under H2 (50 bar) for 48 hours. The solvent was removed under reduced pressure, and the product was separated by column chromatography (silica gel column, eluent: petroleum ether:ethyl acetate = 10:1) to obtain product 2e. HPLC analysis of the product revealed an ee value of 98% and a yield of 94%. HPLC separation conditions: chiral OJ-H column, mobile phase: n-hexane / isopropanol = 99:1 (volume ratio), flow rate: 1.0 mL / min, wavelength: 220 nm, column temperature: 30°C. 1 H NMR (400 MHz, CDCl3) δ 7.19 (t, J = 7.4 Hz, 1H), 7.13 (d, J = 9.2 Hz, 2H), 7.06 (d, J = 7.4 Hz,1H), 4.01-4.20 (m, 2H), 3.08 (d, J = 10.7 Hz, 1H), 2.40 – 2.25 (m, 4H), 1.22(t, J = 7.1 Hz, 3H), 1.04 (d, J = 6.5 Hz, 3H), 0.70 (d, J = 6.7 Hz, 3H). 13C NMR (101MHz, CDCl3) δ 174.1, 138.4, 137.9, 129.1, 128.2, 127.9, 125.5, 60.4, 60.1,31.9, 21.4, 20.3, 14.1. Example 6: Asymmetric reduction of ethyl 2-(3-methoxyphenyl)-3-methylbut-2-enoate

[0045] In a high-purity argon atmosphere, Ni(OAc)2·4H2O (1.0×10 -2 mmol) and ligand ( R,R )-QuinoxP*(1.1×10 -2 mmol) was dissolved in hexafluoroisopropanol (0.5 mL) and stirred at room temperature overnight to obtain an orange-red clear solution (i.e., the catalyst).

[0046] 0.5 mL of the catalyst was added to compound 1f (0.2 mmol), followed by 0.5 mL of hexafluoroisopropanol. The reaction system was placed in an autoclave and stirred at 25°C under H2 (50 bar) for 48 hours. The solvent was removed under reduced pressure, and the product was separated by column chromatography (silica gel column, eluent: petroleum ether:ethyl acetate = 10:1) to obtain product 2f. HPLC analysis of the product revealed an ee value of 93% and a yield of 98%. HPLC separation conditions: chiral OJ-H column, mobile phase: n-hexane / isopropanol = 99:1 (volume ratio), flow rate: 1.0 mL / min, wavelength: 220 nm, column temperature: 30°C. 1H NMR (400 MHz, CDCl3) δ 7.25 – 7.17 (m, 1H), 6.96 – 6.86 (m, 2H), 6.78-6.81 (m, 1H), 4.21 –4.00 (m, 2H), 3.79 (s, 3H), 3.09 (d, J = 10.7 Hz, 1H), 2.27-2.36 (m, 1H), 1.22 (t, J = 7.1 Hz, 3H), 1.03 (d, J = 6.5 Hz, 3H), 0.71 (d, J = 6.7 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 173.8, 159.5, 140.0, 129.2, 120.9, 114.0, 112.5,76.7, 60.5, 60.1, 55.1, 31.9, 21.4, 20.2, 14.1. Example 7: Asymmetric reduction of ethyl 2-(4-fluorophenyl)-3-methylbut-2-enoate

[0047] In a high-purity argon atmosphere, Ni(OAc)2·4H2O (1.0×10 -2 mmol) and ligand ( R,R )-QuinoxP*(1.1×10 -2 mmol) was dissolved in hexafluoroisopropanol (0.5 mL) and stirred at room temperature overnight to obtain an orange-red clear solution (i.e., the catalyst).

[0048] 0.5 mL of the catalyst was added to 1 g (0.2 mmol) of the compound, followed by 0.5 mL of hexafluoroisopropanol. The reaction system was placed in an autoclave and stirred at 25°C under H2 (50 bar) for 48 hours. The solvent was removed under reduced pressure, and the product was separated by column chromatography (silica gel column, eluent: petroleum ether:ethyl acetate = 10:1) to obtain 2 g of the product. HPLC analysis of the product revealed an ee value of 98% and a yield of 60%. HPLC separation conditions: chiral OJ-H column, mobile phase: n-hexane / isopropanol = 99:1 (volume ratio), flow rate: 1.0 mL / min, wavelength: 220 nm, column temperature: 30°C. 1 H NMR (400 MHz, CDCl3) δ 7.34 – 7.27 (m, 2H), 7.03 – 6.95 (m, 2H), 4.20 – 4.02 (m, 2H), 3.11(d, J = 10.6 Hz, 1H), 2.22-2.33 (m, 1H), 1.21 (t, J = 7.1 Hz, 3H), 1.03 (d, J = 6.5Hz, 3H), 0.69 (d, J = 6.7 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 173.9, 134.2,134.1, 129.9, 129.9, 115.3, 115.1, 60.6, 59.3, 32.1, 21.3, 20.1, 14.1. Example 8: Asymmetric reduction of ethyl 2-(4-chlorophenyl)-3-methylbut-2-enoate

[0049] In a high-purity argon atmosphere, Ni(OAc)2·4H2O (1.0×10 -2 mmol) and ligand ( R,R )-QuinoxP*(1.1×10 -2 mmol) was dissolved in hexafluoroisopropanol (0.5 mL) and stirred at room temperature overnight to obtain an orange-red clear solution (i.e., the catalyst).

[0050] 0.5 mL of the catalyst was added to compound 1h (0.2 mmol), followed by 0.5 mL of hexafluoroisopropanol. The reaction system was placed in an autoclave and stirred at 25°C under H2 (50 bar) for 48 hours. The solvent was removed under reduced pressure, and the product was separated by column chromatography (silica gel column, eluent: petroleum ether:ethyl acetate = 10:1) to obtain product 2h. HPLC analysis of the product revealed an ee value of 99% and a yield of 99%. HPLC separation conditions: chiral OJ-H column, mobile phase: n-hexane / isopropanol = 30:0 (volume ratio), flow rate: 1.0 mL / min, wavelength: 220 nm, column temperature: 30°C. 1 H NMR (400 MHz, CDCl3) δ 7.28 (s, 4H), 4.23 – 3.98 (m, 2H), 3.11 (d, J = 10.6 Hz, 1H), 2.25-2.34 (m, 1H), 1.22 (t, J = 7.1 Hz, 3H), 1.03 (d, J = 6.5 Hz, 3H), 0.70 (d, J = 6.7Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 173.6, 136.9, 133.0, 129.8, 128.5, 60.6, 59.4, 32.0, 21.3, 20.1, 14.1. Example 9: Asymmetric reduction of ethyl 3-methyl-2-(3,4,5-trimethoxyphenyl)but-2-enoate

[0051] In a high-purity argon atmosphere, Ni(OAc)2·4H2O (1.0×10 -2 mmol) and ligand ( R,R )-QuinoxP*(1.1×10 -2mmol) was dissolved in hexafluoroisopropanol (0.5 mL) and stirred at room temperature overnight to obtain an orange-red clear solution (i.e., the catalyst).

[0052] 0.5 mL of the catalyst was added to compound 1i (0.2 mmol), followed by 0.5 mL of hexafluoroisopropanol. The reaction system was placed in an autoclave and stirred at 25°C under H2 (50 bar) for 48 hours. The solvent was removed under reduced pressure, and column chromatography (silica gel column, eluent: petroleum ether:ethyl acetate = 10:1) was performed to obtain product 2i. HPLC analysis revealed an ee value of 93% and a yield of 50%. HPLC separation conditions: chiral OJ-H column, mobile phase: n-hexane / isopropanol = 99:1 (volume ratio), flow rate: 1.0 mL / min, wavelength: 220 nm, column temperature: 30°C. 1 H NMR (400 MHz, CDCl3) δ 7.34 – 7.27 (m, 2H), 7.03 – 6.95 (m, 2H), 4.20 – 4.02 (m, 2H), 3.11(d, J = 10.6 Hz, 1H), 2.22-2.33 (m, J = 10.7, 6.6 Hz, 1H), 1.21 (t, J = 7.1 Hz,3H), 1.03 (d, J = 6.5 Hz, 3H), 0.69 (d, J = 6.7 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ174.0, 134.3, 134.3, 130.1, 130.0, 115.5, 115.3, 60.7, 59.5, 32.2, 21.5,20.3, 14.3. Example 10: Asymmetric reduction of ethyl 3-methyl-2-phenylbut-2-enoate

[0053] In a high-purity argon atmosphere, Ni(OAc)2·4H2O (1.0×10 -2 mmol) and ligand ( R,R )-QuinoxP*(1.1×10 -2 mmol) was dissolved in hexafluoroisopropanol (0.5 mL) and stirred at room temperature overnight to obtain an orange-red clear solution (i.e., the catalyst).

[0054] 0.5 mL of the catalyst was added to compound 1j (0.2 mmol), followed by 0.5 mL of hexafluoroisopropanol. The reaction system was placed in an autoclave and stirred at 25°C under H2 (50 bar) for 48 hours. The solvent was removed under reduced pressure, and column chromatography (silica gel column, eluent: petroleum ether:ethyl acetate = 10:1) was performed to obtain product 2j. HPLC analysis of the product revealed an ee value of 96% and a yield of 99%. HPLC separation conditions: chiral OJ-H column, mobile phase: n-hexane / isopropanol = 99:1 (volume ratio), flow rate: 1.0 mL / min, wavelength: 220 nm, column temperature: 30°C. 1 H NMR (400 MHz, CDCl3) δ 7.41 – 7.28 (m, 4H), 7.28 – 7.22 (m, 1H), 4.03-4.19 (m, 2H), 3.14(d, J = 10.6 Hz, 1H), 2.31-2.40 (m, 1H), 1.22 (t, J = 7.1 Hz, 3H), 1.06 (d, J = 6.5Hz, 3H), 0.71 (d, J = 6.7 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 174.1, 138.6,128.6, 128.5, 127.3, 60.58, 60.3, 32.1, 21.5, 20.3, 14.3. Example 11: Asymmetric reduction of ethyl 2-(3-fluorophenyl)-3-methylbut-2-enoate

[0055] In a high-purity argon atmosphere, Ni(OAc)2·4H2O (1.0×10 -2 mmol) and ligand ( R,R )-QuinoxP*(1.1×10 -2 mmol) was dissolved in hexafluoroisopropanol (0.5 mL) and stirred at room temperature overnight to obtain an orange-red clear solution (i.e., the catalyst).

[0056] 0.5 mL of the catalyst was added to compound 1k (0.2 mmol), followed by 0.5 mL of hexafluoroisopropanol. The reaction system was placed in an autoclave and stirred at 25°C under H2 (50 bar) for 48 hours. The solvent was removed under reduced pressure, and the product was separated by column chromatography (silica gel column, eluent: petroleum ether:ethyl acetate = 10:1) to obtain product 2k. HPLC analysis of the product revealed an ee value of 93% and a yield of 96%. HPLC separation conditions: chiral AS-H column, mobile phase: n-hexane / isopropanol = 100:0 (volume ratio), flow rate: 1.0 mL / min, wavelength: 220 nm, column temperature: 30°C. 1 H NMR (400 MHz, CDCl3) δ 7.32 – 7.19 (m, 1H), 7.14 – 7.03 (m, 2H), 6.91-6.96 (m, J = 8.5, 2.5,1.1 Hz, 1H), 4.25 – 3.87 (m, 2H), 3.12 (d, J = 10.6 Hz, 1H), 2.25-2.35 (m, 1H),1.22 (t, J = 7.1 Hz, 3H), 1.03 (d, J = 6.5 Hz, 3H), 0.70 (d, J = 6.7 Hz, 3H). 13 C NMR(101 MHz, CDCl3) δ 173.6, 164.1, 161.7, 141.1, 141.0, 129.9, 129.82, 124.5,124.4, 115.5, 115.3, 114.3, 114.1, 60.8, 59.9, 59.9, 32.2, 21.4, 20.3, 14.2. Example 12: Asymmetric reduction of N-(4-methoxyphenyl)-3-methyl-2-(p-tolyl)but-2-enamide

[0057] In a high-purity argon atmosphere, Ni(OAc)2·4H2O (1.0×10 -2 mmol) and ligand ( R,R )-QuinoxP*(1.1×10 -2 mmol) was dissolved in hexafluoroisopropanol (0.5 mL) and stirred at room temperature overnight to obtain an orange-red clear solution (i.e., the catalyst).

[0058] 0.5 mL of the catalyst was added to compound 11 (0.2 mmol), followed by 0.5 mL of hexafluoroisopropanol. The reaction system was placed in an autoclave and stirred at 25°C under H2 (50 bar) for 48 hours. The solvent was removed under reduced pressure, and column chromatography (silica gel column, eluent: petroleum ether:ethyl acetate = 10:1) was performed to obtain product 21. HPLC analysis of the product revealed an ee value of 98% and a yield of 97%. HPLC separation conditions: chiral OJ-H column, mobile phase: n-hexane / isopropanol = 90:10 (volume ratio), flow rate: 1.0 mL / min, wavelength: 220 nm, column temperature: 30°C. 1 H NMR (400 MHz, CDCl3) δ 7.59 (s, 1H), 7.40 – 7.32 (m, 2H), 7.31 – 7.23 (m, 2H), 7.11 (d, J =7.8 Hz, 2H), 6.82 – 6.71 (m, 2H), 3.74 (s, 3H), 3.00 (d, J = 10.1 Hz, 1H),2.32-2.54 (m, 1H), 2.32 (s, 3H), 1.11 (d, J = 6.5 Hz, 3H), 0.75 (d, J = 6.7 Hz,3H). 13 C NMR (101 MHz, CDCl3) δ 172.0, 156.3, 136.9, 136.2, 131.2, 129.3,128.3, 122.0, 114.0, 62.2, 55.5, 31.6, 21.8, 21.1, 20.5. Example 13: Asymmetric reduction of N-isopropyl-3-methyl-2-(p-tolyl)but-2-enamide

[0059] In a high-purity argon atmosphere, Ni(OAc)2·4H2O (1.0×10 -2 mmol) and ligand ( R,R )-QuinoxP*(1.1×10 -2 mmol) was dissolved in hexafluoroisopropanol (0.5 mL) and stirred at room temperature overnight to obtain an orange-red clear solution (i.e., the catalyst).

[0060] 0.5 mL of the catalyst was added to compound 1m (0.2 mmol), followed by 0.5 mL of hexafluoroisopropanol. The reaction system was placed in an autoclave and stirred at 25°C under H2 (50 bar) for 48 hours. The solvent was removed under reduced pressure, and column chromatography (silica gel column, eluent: petroleum ether:ethyl acetate = 10:1) was performed to obtain product 2m. HPLC analysis of the product revealed an ee value of 93% and a yield of 80%. HPLC separation conditions: chiral OJ-H column, mobile phase: n-hexane / isopropanol = 97:3 (volume ratio), flow rate: 1.0 mL / min, wavelength: 220 nm, column temperature: 30°C. 1 H NMR (400 MHz, CDCl3) δ 7.22 (d, J = 8.1 Hz, 2H), 7.09 (d, J = 8.4 Hz, 2H), 5.38 (d, J = 8.2 Hz,1H), 3.98-4.06 (m, 1H), 2.72 (d, J = 10.1 Hz, 1H), 2.31-2.42 (m, 1H), 2.31 (s,3H), 1.13 (d, J = 6.6 Hz, 3H), 1.02 (d, J = 6.5 Hz, 6H), 0.69 (d, J = 6.7 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 172.7, 136.7, 136.6, 129.2, 128.2, 61.8, 41.4,31.6, 23.0, 22.6, 21.7, 21.2, 20.6. Example 14: Asymmetric reduction of 2-(4-isopropylphenyl)-N-(4-methoxyphenyl)-3-methylbut-2-enamide

[0061] In a high-purity argon atmosphere, Ni(OAc)2·4H2O (1.0×10 -2 mmol) and ligand ( R,R )-QuinoxP*(1.1×10 -2 mmol) was dissolved in hexafluoroisopropanol (0.5 mL) and stirred at room temperature overnight to obtain an orange-red clear solution (i.e., the catalyst).

[0062] 0.5 mL of the catalyst was added to compound 1n (0.2 mmol), followed by 0.5 mL of hexafluoroisopropanol. The reaction system was placed in an autoclave and stirred at 25°C under H2 (50 bar) for 48 hours. The solvent was removed under reduced pressure, and the product was separated by column chromatography (silica gel column, eluent: petroleum ether:ethyl acetate = 10:1) to obtain product 2n. HPLC analysis of the product revealed an ee value of 91% and a yield of 99%. HPLC separation conditions: chiral OD-H column, mobile phase: n-hexane / isopropanol = 30:0 (volume ratio), flow rate: 1.0 mL / min, wavelength: 220 nm, column temperature: 30°C. 1 H NMR (400 MHz, CDCl3) δ 7.40 – 7.34 (m, 3H), 7.33 – 7.27 (m, 2H), 7.20 – 7.13 (m, 2H), 6.83– 6.74 (m, 2H), 3.75 (s, 3H), 2.97 (d, J = 10.0 Hz, 1H), 2.88 (q, J = 6.9 Hz,1H), 2.56 – 2.42 (m, 1H), 1.23 (d, J = 6.9 Hz, 6H), 1.10 (d, J = 6.5 Hz, 3H),0.75 (d, J = 6.9 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 171.8, 156.2, 147.7, 136.3,131.1, 128.2, 126., 121.7, 113.9, 62.2, 55.4, 33.7, 31.5, 23.9, 23.9, 21.7,20.4. Example 15: Asymmetric reduction of N-2-bis(4-methoxyphenyl)-3-methylbut-2-enamide

[0063] In a high-purity argon atmosphere, Ni(OAc)2·4H2O (1.0×10 -2 mmol) and ligand ( R,R )-QuinoxP*(1.1×10 -2 mmol) was dissolved in hexafluoroisopropanol (0.5 mL) and stirred at room temperature overnight to obtain an orange-red clear solution (i.e., the catalyst).

[0064] 0.5 mL of the catalyst was added to compound 1o (0.2 mmol), followed by 0.5 mL of hexafluoroisopropanol. The reaction system was placed in an autoclave and stirred at 25°C under H2 (50 bar) for 48 hours. The solvent was removed under reduced pressure, and the product was separated by column chromatography (silica gel column, eluent: petroleum ether:ethyl acetate = 10:1) to obtain product 2o. HPLC analysis of the product revealed an ee value of 92% and a yield of 99%. HPLC separation conditions: chiral OD-H column, mobile phase: n-hexane / isopropanol = 95:5 (volume ratio), flow rate: 1.0 mL / min, wavelength: 220 nm, column temperature: 30°C. 1 H NMR (400 MHz, CDCl3) δ 7.39 (dd, J = 9.4, 2.5 Hz, 3H), 7.35 – 7.30 (m, 2H), 6.90 – 6.84 (m,2H), 6.84 – 6.78 (m, 2H), 3.79 (d, J = 13.5 Hz, 6H), 2.97 (d, J = 10.0 Hz, 1H),2.43-2.52 (m, 1H), 1.11 (d, J = 6.5 Hz, 3H), 0.76 (d, J = 6.7 Hz, 3H). 13 C NMR (101MHz, CDCl3) δ 171.9, 158.7, 156.3, 131.2, 131.1, 129.3, 121.7, 114.0, 113.9,61.7, 55.43, 55.21, 31.6, 21.6, 20.3. Example 16: Asymmetric reduction of 2-(3-methoxyphenyl)-N-(4-methoxyphenyl)-3-methylbut-2-enamide

[0065] In a high-purity argon atmosphere, Ni(OAc)2·4H2O (1.0×10 -2 mmol) and ligand ( R,R )-QuinoxP*(1.1×10 -2 mmol) was dissolved in hexafluoroisopropanol (0.5 mL) and stirred at room temperature overnight to obtain an orange-red clear solution (i.e., the catalyst).

[0066] 0.5 mL of the catalyst was added to compound 1p (0.2 mmol), followed by 0.5 mL of hexafluoroisopropanol. The reaction system was placed in an autoclave and stirred at 25°C under H2 (50 bar) for 48 hours. The solvent was removed under reduced pressure, and column chromatography (silica gel column, eluent: petroleum ether:ethyl acetate = 10:1) was performed to obtain product 2p. HPLC analysis of the product revealed an ee value of 91% and a yield of 99%. HPLC separation conditions: chiral OD-H column, mobile phase: n-hexane / isopropanol = 95:5 (volume ratio), flow rate: 1.0 mL / min, wavelength: 220 nm, column temperature: 30°C. 1 H NMR (400 MHz, CDCl3) δ 7.47 (s, 1H), 7.40 – 7.29 (m, 2H), 7.22 (t, J = 7.9 Hz, 1H), 7.00 –6.93 (m, 2H), 6.82 – 6.74 (m, 3H), 3.76 (d, J = 14.8 Hz, 6H), 2.97 (d, J = 10.2Hz, 1H), 2.44-2.53 (m, 1H), 1.10 (d, J = 6.5 Hz, 3H), 0.75 (d, J = 6.7 Hz, 3H). 13 CNMR (101 MHz, CDCl3) δ 171.4, 159.7, 156.3, 140.7, 131.0, 129.4, 121.8,120.7, 114.0, 113.9, 113.8, 112.5, 62.5, 55.4, 55.1, 31.6, 21.6, 20.4. Example 17 Ligand Screening: Step 1: In a high-purity argon atmosphere, Ni(OAc)2 (0.2×10 -2 mmol) and ligand (0.22×10 -2 mmol) was dissolved in 1.0 mL of the ligand shown in Table 1, and the mixture was stirred at room temperature for 12 hours to obtain a catalyst solution.

[0067] Step 2: 1 mL of the clear solution was added to compound 1a (0.2 mmol), and the reaction system was placed in an autoclave and stirred at 25 °C under H2 (50 bar) for 48 h.

[0068] Step 3: Remove the solvent under reduced pressure and separate by column chromatography (using silica gel column, eluent: petroleum ether: ethyl acetate = 20:1) to obtain product 1b. The product was analyzed by HPLC and the ee value was measured. HPLC separation conditions: chiral OJ-H column, mobile phase: n-hexane / isopropanol = 99:1 (volume ratio), flow rate: 1.0 mL / min, wavelength: 220 nm, column temperature: 30°C.

[0069]

[0070] Table 1: Ligand screening table

[0071] Example 17 shows that for the Ni(OAc)2 / Ligand catalytic system, under the same substrate / catalyst ratio, reaction temperature and hydrogen pressure, different bisphosphine chiral ligands produce different enantiomeric amounts. ( R , R )-QuinoxP* can achieve better results.

[0072] Example 18 Metal Screening: Step 1: In a high-purity argon atmosphere, metal nickel compounds (0.2×10 -2 mmol) and ligand ( R , R )-QuinoxP* (0.22×10 -2 mmol) was dissolved in 1 mL of trifluoroethanol and stirred at room temperature for 12 hours to obtain a catalyst solution.

[0073] Step 2: 1 mL of the clear solution was added to compound 1a (0.2 mmol), and the reaction system was placed in an autoclave and stirred at 25°C under H2 (50 bar) for 48 hours.

[0074] Step 3: Remove the solvent under reduced pressure and separate by column chromatography (using a silica gel column, the eluent is petroleum ether:ethyl acetate = 20:1) to obtain product 1b. The product is analyzed by HPLC and the ee value is measured. Metal screening table 2: HPLC separation conditions: chiral OJ-H column, mobile phase: n-hexane / isopropanol = 99:1 (volume ratio), flow rate: 1.0 mL / min, wavelength: 220 nm, column temperature: 30°C.

[0075]

[0076] Table 2: Metal Screening Table

[0077] As can be seen from Example 18, for the use of [Ni] / ( R , R )-QuinoxP* catalytic system, under the same substrate / catalyst ratio, reaction temperature and hydrogen pressure, different metal precursors produced different enantiomeric amounts, and Ni(OAc)2·4H2O could obtain better results.

[0078] Example 19 Solvent screening: Step 1: In a high-purity argon atmosphere, Ni(OAc)2·4H2O (0.2×10 -2 mmol) and ligand ( R , R )-QuinoxP* (0.22×10 -2 mmol) was dissolved in 1.0 mL of Solvent shown in Table 3, and the mixture was stirred at room temperature for 12 hours to obtain a catalyst solution.

[0079] Step 2: 100 μL of the clear solution was added to compound 1a (0.2 mmol) and 1 mL of Solvent, the same solvent used in step 1. The reaction system was placed in an autoclave and stirred at 25 °C under H2 (50 bar) for 48 hours.

[0080] Step 3: Remove the solvent under reduced pressure and separate by column chromatography (using a silica gel column, the eluent is petroleum ether: ethyl acetate = 20:1) to obtain product 1b. The product is analyzed by HPLC and the ee value is measured. Solvent screening table 3 is obtained: HPLC separation conditions: chiral OJ-H column, mobile phase: n-hexane / isopropanol = 99:1 (volume ratio), flow rate: 1.0 mL / min, wavelength: 220 nm, column temperature: 30°C.

[0081]

[0082] Table 3: Solvent screening table

[0083] a: 25 o C As can be seen from Example 19, for the use of Ni(OAc)2·4H2O / ( R , R )-QuinoxP* catalytic system, under the same substrate / catalyst ratio, reaction temperature and hydrogen pressure, different solvents produced different enantiomeric amounts, and THF and HFIP could obtain better results.

[0084] Example 20: Ni(OAc)2·4H2O / ( R,R Applicability of )-QuinoxP* catalyst Step 1: In a high-purity argon atmosphere, Ni(OAc)2·4H2O and ( R,R )-QuinoxP* was dissolved in 1 ml of HFIP and stirred at room temperature for 12 hours to obtain an orange-red clear solution.

[0085] Step 2: Add 500 μL of the clear solution to compounds 1a-1o (0.2 mmol) and 500 μL of HFIP. Place the reaction system in an autoclave and stir at 25°C under H2 (50 bar) for 48 hours.

[0086] Step 3: Remove the solvent under reduced pressure and separate by column chromatography (using silica gel column, eluent: petroleum ether:ethyl acetate = 9:1) to obtain products 2a~2n, respectively. The products were analyzed by HPLC to determine the ee values ​​of 2a~2o, respectively.

[0087] HPLC separation conditions: chiral OJ-H column, mobile phase: n-hexane / isopropanol = 99:1 (volume ratio), flow rate: 1.0 mL / min, wavelength: 220 nm, column temperature: 30°C.

[0088] Ni(OAc)2·4H2O / ( R,R )-QuinoxP* catalyst has different applicability for different substrates. The results are shown in the above formula. Substrates 1a~1o, various olefins give the corresponding chiral carboxylates 2a~2o with good conversion and enantioselectivity (>70% conv., 91%-99%). Ni(OAc)2·4H2O / ( R,R The )-QuinoxP* catalyst tolerates different electronic properties (electron neutral, electron-rich, and electron-deficient) on the phenyl group and has good effects on different phenyl substituents. At the same time, when the hydrogen at specific positions on the tetrasubstituted olefin ring is replaced by a chain alkyl group, it can also hydrogenate with high conversion and high selectivity to produce specific chiral carboxylic acid derivatives.

[0089] The above-described embodiments are only used to illustrate the technical solutions of the present application, rather than to limit them. Although the present application has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the aforementioned embodiments, or make equivalent replacements for some of the technical features therein. These modifications or replacements do not deviate the essence of the corresponding technical solutions from the spirit and scope of the technical solutions of the various embodiments of the present application, and should all be included in the scope of protection of the present application.

Claims

1. A method for the asymmetric hydrogenation of tetrasubstituted α,β-unsaturated carboxylic acid derivatives catalyzed by nickel, characterized in that: The steps include: The compound represented by formula (I) is asymmetrically hydrogenated in the presence of a catalyst Cat to obtain the compound represented by formula (II). The reaction formula is shown below: ； The catalyst Cat is prepared from a metal nickel compound and a diphosphorus chiral ligand, wherein the diphosphorus chiral ligand is selected from the following Any one of the structural formulas shown, The above * represents a carbon chiral center, and the multiple carbon chiral centers are each independently of the R configuration or the S configuration.

2. The method according to claim 1, characterized in that The R 1 、R 2 is selected from substituted or unsubstituted monocyclic carbocyclic groups, substituted or unsubstituted fused-ring carbocyclic groups, substituted or unsubstituted spirocyclic groups, substituted or unsubstituted bridged rings, substituted or unsubstituted monocyclic heterocyclic groups, substituted or unsubstituted fused-ring heterocyclic groups, substituted or unsubstituted monocyclic aryl groups, substituted or unsubstituted branched-chain alkyl groups, and substituted or unsubstituted straight-chain alkyl groups; The n is a straight chain alkane with 1-6.

3. The method according to claim 1, characterized in that The R 1 is cyclohexyl, furyl, thienyl, pyridyl, naphthyl, or phenyl; each of the cyclohexyl, furyl, thienyl, pyridyl, naphthyl, or phenyl is optionally substituted by one or more groups independently selected from nitro, fluorine, chlorine, bromine, C1-C4 alkyl, C1-C4 halo, and C1-C4 alkoxy; And / or, the R 1 is cyclohexyl, 2-furyl, 2-thienyl, 2-pyridyl, 1-naphthyl, 2-naphthyl, phenyl, 4-methylphenyl, 4-fluorophenyl, 3-fluorophenyl, 2-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-nitrophenyl, 4-trifluoromethylphenyl, 3,5-bis(trifluoromethyl)phenyl, 4-methoxyphenyl, 3-methoxyphenyl; The R 2 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxyacylmethyl, methoxyacylethyl, ethoxyacylmethyl or ethoxyacylethyl.

4. The method according to any one of claims 1 to 3, characterized in that The n is a straight chain alkyl group of 1-6, and the structure is shown below: The R is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, fluorine, chlorine, bromine, or alkoxy.

5. The method according to claim 1, wherein: The tetrasubstituted α,β-unsaturated carboxylic acid derivative is one of the structures shown below: 。 6. The method according to claim 1, characterized in that The metal nickel compound includes any one of Ni(OAc)2·4H2O, Ni(OAc)2, NiCl2(DME), NiBr2(DME), Ni(OTf)2, Ni(acac)2, Ni(OCOCF3)2·6H2O, and NiI2.

7. The method according to claim 1, characterized in that The metal nickel compound and the diphosphorus chiral ligand are reacted in a solvent Solvent at room temperature for 0.5 hour to 12 hours to prepare a metal catalyst.

8. The method according to claim 7, characterized in that The solvent is methanol, ethanol, isopropanol, tert-butanol, dichloromethane, toluene, 1,2-dichloroethane, chloroform, carbon tetrachloride, tetrahydrofuran, 1,4-dioxane, n-hexane or cyclohexane, or a combination thereof.

9. The method according to claim 7, characterized in that The molar ratio of the metal nickel compound to the diphosphorus chiral ligand is 1.0:1.0-1.

2.

10. The method according to claim 1, characterized in that The reaction temperature of the asymmetric reduction is 0°C to 50°C, preferably below 25°C; and / or the reaction time of the asymmetric reduction is 1h to 48h, preferably 48h; and / or the asymmetric reduction is carried out in a hydrogen atmosphere at 45 to 55 atmospheres of pressure.

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